8/8/2019 Ch6 Immune

1/81

Diseases of IMMUNITY

8/8/2019 Ch6 Immune

2/81

OBJECTIVES Differentiate between the concepts of

Innate and Adaptive immunity

Visually recognize and understand the basic

roles of lymphocytes, macrophages,dendritic cells, NK cells

Understand the roles of the major cytokines

in immunity Differentiate and give examples of the four

(4) different types of hypersensitivity

reactions

8/8/2019 Ch6 Immune

3/81

OBJECTIVES Know the common features of autoimmune

diseases, and the usual four (4) mainfeatures (Etiology, Pathogenesis,Morphology, and Clinical Expression) of

Systemic Lupus Erythematosus,Rheumatoid Arthritis, Sjgrens, SystemicSclerosis (Scleroderma), Mixed Connective

Tissue Disease, and Poly- (aka, Peri-) -arteritis Nodosa Differentiate between Primary (Genetic) andSecondary (Acquired) Immunodeficiencies

8/8/2019 Ch6 Immune

4/81

OBJECTIVES Understand the usual four (4) main features

of AIDS, i.e., etiology, pathogenesis,morphology, clinical expression

Understand the usual four (4) main featuresof Amyloidosis

8/8/2019 Ch6 Immune

5/81

IMMUNITY INNATE (present beforebirth, NATURAL)

ADAPTIVE (developedby exposure to pathogens,or in a broader sense,antigens)

8/8/2019 Ch6 Immune

6/81

MHC

MajorHistocompatibility Complex A genetic LOCUS on Chromosome 6,

which codes for cell surface compatibility Also called HLA (Human Leukocyte

Antigens) in humans and H-2 in mice

Its major job is to make sure all self cellantigens are recognized and tolerated,because the general rule of the immunesystem is that all UN-recognized cells will

NOT be tolerated

8/8/2019 Ch6 Immune

7/81

INNATE IMMUNITY BARRIERS

CELLS: LYMPHOCYTES,MACROPHAGES, PLASMA CELLS,

NK CELLS

CYT

OKIN

ES/CHE

MO

KINES

PLASMA PROTEINS:Complement, Coagulation Factors

Toll-Like Receptors, TLRs

8/8/2019 Ch6 Immune

8/81

ADAPTIVE

IMMUNITY

CELLULAR, i.e., directcellular reactions toantigens

HUMORAL, i.e.,

antibodies

8/8/2019 Ch6 Immune

9/81

8/8/2019 Ch6 Immune

10/81

CELLS of the IMMUNESYSTEM

LYMPHOCYTES, T

LYMPHOCYTES,B

PLASMA CELLS(MODIFIED BCELLS) MACROPHAGES, aka HISTIOCYTES,

(APCs, i.e., Antigen Presenting Cells)

DENDRITIC CELLS (APCs, i.e., AntigenPresenting Cells)

NK (NATURAL KILLER)CELLS

8/8/2019 Ch6 Immune

11/81

L

Y

M

P

H

S

8/8/2019 Ch6 Immune

12/81

8/8/2019 Ch6 Immune

13/81

ANY ROUND CELL WITH RATHER

DENSESTAINING NUCLEUS AND

MINIMAL CYTOPLASM INCONNECTIVE TISSUE, A BIT

BIGGER THAN AN RBC, IS A

LYMPHOCYTEUNTIL PROVEN OTHERWISE

8/8/2019 Ch6 Immune

14/81

MACROPHAGE

aka

HISTIOCYTE

8/8/2019 Ch6 Immune

15/81

MACROPHAGES are

MONOCYTES that have come

out of circulation and have

gone into tissue

8/8/2019 Ch6 Immune

16/81

MACROPHAGES, TEM, SEM

8/8/2019 Ch6 Immune

17/81

ANY CELL MIXED IN WITH LYMPHOCYTESBUT HAS

A LARGER MORE OPEN, LESS DENSE, LESS

CIRCULAR NUCLEUS WITH MORECYTOPLASM IS A

MAC

RO

PHAGE

UNTIL PROVEN OTHERWISE

ALMOST ALL GRANULAR or PIGMENTEDCELLS IN CONNECTIVE TISSUE ARE

MACROPHAGES. GRANULOMAS, GIANT CELLS,

ARECHIEFLY MACROPHAGES ALSO.

8/8/2019 Ch6 Immune

18/81

1) ROUND NUCLEUS

2) OVOID CYTOPLASM

3) PERIPHERAL CHROMATIN

4) CLEAR ZONE BETWEEN NUCLEUS AND WIDER LIP OF

CYTOPLASM

PLASMA CELLS

8/8/2019 Ch6 Immune

19/81

8/8/2019 Ch6 Immune

20/81

NKCE

LLS

8/8/2019 Ch6 Immune

21/81

8/8/2019 Ch6 Immune

22/81

GENERAL SCHEME of

CELLULAR EVENTS APCs (Macrophages, DendriticCells)

T-Cells (Control Everything)

CD4 REGULATORS (Helper)

CD8 EFFECTORS

B-Cells Plasma Cells ABs

NK Cells

8/8/2019 Ch6 Immune

23/81

8/8/2019 Ch6 Immune

24/81

CYT

OKIN

ES MEDIATE INNATE (NATURAL)

IMMUNITY, IL-1, TNF, INTERFERONS

REGULATE LYMPHOCYTE GROWTH(many interleukins, ILs)

ACTIVATE INFLAMMATORY CELLS STIMULATE HEMATOPOESIS,

(CSFs, orColonyStimulating Factors)

8/8/2019 Ch6 Immune

25/81

CYTOKINES/CHEMOKINES

CYTOKINES are PROTEINS produced byMANY cells, but usually LYMPHOCYTESand MACROPHAGES, numerous roles in

acute and chronic inflammation, ANDimmunity

TNF,

IL-1, by

macrophages CHEMOKINESare small proteins which are

attractants for PMNs

8/8/2019 Ch6 Immune

26/81

MHC

MajorHistocompatibility Complex A genetic LOCUS on Chromosome 6,

which codes for cell surface compatibility Also called HLA (Human Leukocyte

Antigens) in humans and H-2 in mice

Its major job is to make sure all self cellantigens are recognized and tolerated,because the general rule of the immunesystem is that all UN-recognized cells will

NO

T be tolerated

8/8/2019 Ch6 Immune

27/81

8/8/2019 Ch6 Immune

28/81

MHC MOLECULES

(Gene Products) I (All nucleated cells and platelets), cell surface

glycoproteins, ANTIGENS

II (APCs, i.e., macs and dendritics, lymphs),cell surface glycoproteins, ANTIGENS

III Complement System Proteins

8/8/2019 Ch6 Immune

29/81

IMMUNESYSTEM DISORDERS

WHATC

AN GO

WRO

NG? HYPERSENSITIVITY REACTIONS, I-IV

AUTO-IMMUNE DISEASES, aka

COLLAGEN DISEASES (BADTERM)

IMMUNE DEFICIENCY SYNDROMES,

IDS: PRIMARY (GENETIC)

SECONDARY (ACQUIRED)

8/8/2019 Ch6 Immune

30/81

HYPERSENSITIVITY

REACTIONS (4) I (Immediate Hypersensitivity)

II (Antibody MediatedHypersensitivity)

III (Immune-Complex MediatedHypersensitivity)

IV (Cell-Mediated Hypersensitivity)

8/8/2019 Ch6 Immune

31/81

Type I

IMMEDIATE HYPERSENSITIVITY Immediate means seconds to minutes

Immediate Allergic Reactions, which maylead to anaphylaxis, shock, edema, dyspnea

death1) Allergen exposure

2) IMMEDIATE phase: MAST cellDEgranulation, vasodilatation, vascularleakage, smooth muscle (broncho)-spasm

3) LATE phase (hours, days):Eosinophils,PMNs, T-Cells

8/8/2019 Ch6 Immune

32/81

TYPE II HYPERSENSITIVITY

ANTIBODY MEDIATED IMMUNITY

ABs attach to cell surfaces

OPSONIZATION (basting the turkey)

PHAGOCYTOSISCOMPLEMENT FIXATION (cascade of

C1q, C1r, C1s, C2,C3, C4, C5.. ) LYSIS (destruction of cells by

rupturing or breaking of the cell

membrane)

8/8/2019 Ch6 Immune

33/81

TYPE II DISEASES Autoimmune Hemolytic Anemia, AHA Idiopathic Thrombocytopenic Purpura,

ITP

Goodpasture Syndrome (Nephritis andLung hemorrhage)

Rheumatic Fever

Myasthenia Gravis

Graves Disease

Pernicious Anemia, PA

8/8/2019 Ch6 Immune

34/81

TYPE III HYPERSENSITIVITY

IMMUNECOMPLEX MEDIATED Antigen/Antibody Complexes

Where do they go?

Kidney (GlomerularBasement Membrane)

Blood Vessels Skin

Joints

C

ommon Type III Diseases-S

LE

(Lupus),Poly(Peri)arteritis Nodosa,Poststreptococcal Glomerulonephritis,Arthus reaction (hrs), Serum sickness

(days)

8/8/2019 Ch6 Immune

35/81

TYPE IV HYPERSENSITIVITY

CELL-MEDIATED (T-CELL)

DELAYED HYPERSENSITIVITY Tuberculin Skin Reaction

DIRECT ANTIGENCELL CONTACT

GRANULOMA FORMATION

CONTACT DERMATITIS

8/8/2019 Ch6 Immune

36/81

8/8/2019 Ch6 Immune

37/81

SUMMARY I Acute allergic reaction

II Antibodies directed against cellsurfaces

III Immune complexes

IV Delayed Hypersensitivity, e.g., Tb

skin test

8/8/2019 Ch6 Immune

38/81

RENAL

TRANSPLANT REJECTION

HYPERACUTE (minutes) :AG/ABreaction of vascular endothelium

ACUTE (days months):cellular(INTERSTITIAL infiltrate) and humoral(VASCULITIS)

CHRONIC (months):slow vascularfibrosis

8/8/2019 Ch6 Immune

39/81

ACUTECELLULAR (T) ACUTE HUMORAL

CHRONIC

8/8/2019 Ch6 Immune

40/81

AUTO-IMMUNE DISEASES

Failure of SELF RECOGNITION Failure ofSELF TOLERANCE

TOLERANCE

CENTRAL (Death of self reactive lymphocytes)

PERIPHERAL (anergy, suppression by T-cells,deletion by apoptosis, sequestration (Ag masking))

STRONG GENETIC PREDISPOSITION OFTEN RELATED TOOTHERAUTOIMMUNE

DISEASES

OFTEN TRIGGERED BY INFEC

TIO

NS

CLASSIC AUTOIMMUNE

8/8/2019 Ch6 Immune

41/81

CLASSIC AUTOIMMUNE

DISEASES (SYSTEMIC)LUPUS (SLE) Systemic LupusErythematosus

RHEUMATOID ARTHRITIS

SJGREN SYNDROME

SYSTEMICSCLEROSIS (scleroderma)

collagen diseases (term no longer

used)

CLASSIC AUTOIMMUNE

8/8/2019 Ch6 Immune

42/81

CLASSIC AUTOIMMUNE

DISEASES (LOCAL) HASHIMOTO THYROIDITIS AUTOIMMUNE HEMOLYTIC ANEMIA

MULTIPLESCLEROSIS AUTOIMMUNEORCHITIS

GOODPASTURESYNDROME

AUTOIMMUNE THROMBOCYTOPENIA

PERNICIOUS ANEMIA

INSULIN DEPENDENT DIABETES MELLITUS

MYASTHENIA GRAVIS

GRAVES DISEASE

8/8/2019 Ch6 Immune

43/81

N.B. The list of diseases

proven to beautoimmune grows

by leaps and boundsevery year!!!

8/8/2019 Ch6 Immune

44/81

LUPUS

(S

LE

) Etiology: Antibodies (ABs) directed againstthe patients own DNA, HISTONES, NON-histone RNA, and NUCLEOLUS

Pathogenesis: Progressive DEPOSITION

and INFLAMMATION to immune deposits, in

skin, joints, kidneys, vessels, heart, CNS

Morphology: Butterfly rash, skin deposits,

glomerolunephritis (NOT discoid)

Clinical expression: Progressive renal and

vascular disease, POSITIVE A.N.A.

8/8/2019 Ch6 Immune

45/81

H R

8/8/2019 Ch6 Immune

46/81

H

O

MO

S

P

E

C

K

R

I

M

N

U

C

L

E

O

L

A

R

8/8/2019 Ch6 Immune

47/81

SLE, SKIN SLE, GLOMERULUS

8/8/2019 Ch6 Immune

48/81

TABLE 6-10 -- Clinical and Pathologic Manifestations of Systemic Lupus

8/8/2019 Ch6 Immune

49/81

TABLE 6-10 -- Clinical and Pathologic Manifestations ofSystemic Lupus

Erythematosus

Clinical Manifestation

Preval

ence

in

Patients, %

Hematologic 100

Arthritis 90

Skin 85

Fever 83Fatigue 81

Weight loss 63

Renal 50

Central nervous system 50

Pleuritis 46Myalgia 33

Pericarditis 25

Gastrointestinal 21

Raynaud phenomenon 20

Ocular 15

Peripheral neuropathy 14

8/8/2019 Ch6 Immune

50/81

MORESYSTEMIC

AUTOIMMUNEDISEASES

RHEUMATOID ARTHRITIS

SJGREN SYNDROME

SCLERODERMA (SYSTEMIC

SCLEROSIS)

8/8/2019 Ch6 Immune

51/81

NORMAL Bi-Layered

Synovium

Destructive

Rheumatoid Synovitis

8/8/2019 Ch6 Immune

52/81

SJGRENSYNDROME

8/8/2019 Ch6 Immune

53/81

8/8/2019 Ch6 Immune

54/81

8/8/2019 Ch6 Immune

55/81

SCLERODERMA

(SYSTEMICSCLEROSIS)

8/8/2019 Ch6 Immune

56/81

SYSTEMICSCLEROSIS

(SCLERODERMA)

MORE AUTOIMMUNE

8/8/2019 Ch6 Immune

57/81

MORE AUTOIMMUNE

DISEASES (LOCAL) HASHIMOTO THYROIDITIS AUTOIMMUNE HEMOLYTIC ANEMIA

MULTIPLESCLEROSIS

AUTOIMMUNEORCHITIS

GOODPASTURESYNDROME

AUTOIMMUNE THROMBOCYTOPENIA (ITP)

PERNICIOUS ANEMIA INSULIN DEPENDENT DIABETES MELLITUS (I)

MYASTHENIA GRAVIS

GRAVES DISEASE

I D

8/8/2019 Ch6 Immune

58/81

ImmunoDefiency

Syndromes (-IDS)

PRIMARY (GE

NE

TIC

)(P-IDS?)

SECONDARY(ACQUIRED) (A-IDS)

PRIMARY

8/8/2019 Ch6 Immune

59/81

PRIMARY CHILDREN with repeated, often severe

infections, cellular AND/OR humoralimmunity problems, autoimmune defects

BRUTON (X-linked agammaglobulinemia)

COMMON VARIABLE

IgA deficiency

Hyper -IgM

DI GEORGE (THYMIC HYPOPLASIA) 22q11.2

SCID (Severe Combined Immuno Deficiency) .with thrombocytopenia and eczema

(WISKOTT-ALDRICH)

COMPLEMENT DEFICIENCIES

8/8/2019 Ch6 Immune

60/81

ADA=

ADE

NOS

INE

DEAMINASE

Examples of Infections in Immunodeficiencies

8/8/2019 Ch6 Immune

61/81

Examples of Infections in Immunodeficiencies

Pathogen Type T-Cell-Defect B-Cell DefectGranulocyte

Defect Complement DefectBacteria Bacterial sepsis Streptococci,

staphylococci,

Haemophilus

Staphylococci,

Pseudomon

as

Neisserial

infections,other pyogenic

bacterial

infectionsViruses Cytomegalovirus,

Epstein-Barr virus,

severe varicella,chronic infections with

respiratory and

intestinal viruses

Enteroviralencephalitis

Fungi and

parasitesCandida, Pneumocystis

carinii

Severe intestinalgiardiasis

Candida,

Nocardia,

AspergillusSpecial features Aggressive disease

with opportunistic

pathogens, failure to

clear infections

Recurrent

sinopulmonary

infections,

sepsis, chronic

meningitis

AIDS

8/8/2019 Ch6 Immune

62/81

AIDS(SECONDARY IDS) Etiology: HIV

Pathogenesis: Infection, Latency,

Progressive T-Cell loss Morphology: MANY

Clinical Expressions: Infections,Neoplasms, Progressive Immune Failure,

Death, HIV+, HIV-RNA (Viral Load)

8/8/2019 Ch6 Immune

63/81

EPIDEMIOLOGY HOMOSEXUAL (40%, and

declining)

INTRAVENOUS DRUG

USAGE (25%)

HETEROSEXUAL SEX (10%

and rising)

ETIOLOGY

8/8/2019 Ch6 Immune

64/81

ETIOLOGY

8/8/2019 Ch6 Immune

65/81

PATHOGENESIS

ATTACHING BUDDING

PATHOGENESIS

8/8/2019 Ch6 Immune

66/81

PATHOGENESIS

EARLY BUDDING

PATHOGENESIS

8/8/2019 Ch6 Immune

67/81

PATHOGENESIS

LATE BUDDING

PATHOGENESIS

8/8/2019 Ch6 Immune

68/81

PATHOGENESIS

MATURE NEW VIRIONS

8/8/2019 Ch6 Immune

69/81

REVERSE TRANSCRIPTASE

The enzyme reverse transcriptase(RT) is used by retroviruses totranscribe their single-strandedRNA genome into single-strandedDNA and to subsequentlyconstruct a complementary strand

of DNA, providing a DNA doublehelix capable of integration intohost cell chromosomes.

8/8/2019 Ch6 Immune

70/81

PATHOGENESIS

PATHOGENESIS

8/8/2019 Ch6 Immune

71/81

PATHOGENESIS

1) PRIMARY INFECTION

2) LYMPHOID INFECTION

3) AC

UTE

SYNDR

OME

4) IMMUNE RESPONSE

5) LATENCY

6) AIDS

8/8/2019 Ch6 Immune

72/81

GENERAL IMMUNE

8/8/2019 Ch6 Immune

73/81

GENERAL IMMUNE

ABNORMALITIES LYMPHOPENIA

DECREASED T-CELL

FUNCTION B-CELL ACTIVATION,

POLYCLONAL

ALTEREDMONOCYTE/MACROPHAGE

FUNCTION

INFECTIONS

8/8/2019 Ch6 Immune

74/81

INFECTIONS Protozoal/Helminthic:Cryptosporidium, PCP

(PneumocystisC

ariniiPneumonia), Toxoplasmosis

Fungal: Candida, and the usual 3

Bacterial: TB, Nocardia,

Salmonella

Viral: CMV, HSV, VZ (Herpes Family)

8/8/2019 Ch6 Immune

75/81

PCP

8/8/2019 Ch6 Immune

76/81

CRYPT

OSPO

RIDIUM

8/8/2019 Ch6 Immune

77/81

CASE

ATING GRANULO

MA

CANCERS f AIDS

8/8/2019 Ch6 Immune

78/81

CANCERS of AIDS

KAPOSI SARCOMA

B-CELL LYMPHOMAS

CNS LYMPHOMAS

CE

RVIXC

ANCE

R,SQUAMOUSCELL

AMYLOIDOSIS

8/8/2019 Ch6 Immune

79/81

AMYLOIDOSIS BUILDUP OF AMYLOID PROTEIN

AL (Amyloid Light Chain)

AA (NON-immunoglobulin protein)

A (Alzheimers)

WHERE? BLOOD VESSEL WALLS, at first

KIDNEY

SPLEEN

LIVER

HEART

8/8/2019 Ch6 Immune

80/81

CONGO RED STAIN, WITHOUT,

and WITH, POLARIZATION

AMYLOID ASSOCIATIONS

8/8/2019 Ch6 Immune

81/81

AMYLOID ASSOCIATIONS

PLASMA CELL DYSCRASIAS, i.e.,MULTIPLEMYELOMA

CHRONIC GRANULOMATOUS

DISEASE, e.g., TB HEMODIALYSIS

HEREDOFAMILIAL

LOCALIZED ENDOCRINEMEAs (Multiple Endocrine

Adenomas)